JP2002515421A - Pharmaceutical preparations containing levothyroxine sodium - Google Patents

Pharmaceutical preparations containing levothyroxine sodium

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Publication number
JP2002515421A
JP2002515421A JP2000549216A JP2000549216A JP2002515421A JP 2002515421 A JP2002515421 A JP 2002515421A JP 2000549216 A JP2000549216 A JP 2000549216A JP 2000549216 A JP2000549216 A JP 2000549216A JP 2002515421 A JP2002515421 A JP 2002515421A
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Prior art keywords
sodium
formulation
levothyroxine sodium
levothyroxine
filler
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JP4709379B2 (en
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スヴェン シュレーダー、
マリオン ニシュヴィッツ、
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Merck Patent GmbH
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Merck Patent GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2063—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

(57)【要約】 本発明は、レボチロキシンナトリゥム、ゼラチン及び充填剤を含み有機溶媒残留物の存在しない医薬製剤に関し、さらにその製造方法に関する。   (57) [Summary] The present invention relates to a pharmaceutical preparation containing levothyroxine sodium, gelatin and a filler and free of organic solvent residues, and further relates to a method for producing the same.

Description

【発明の詳細な説明】DETAILED DESCRIPTION OF THE INVENTION

【０００１】 （技術分野） この発明は、レボチロキシンナトリゥム、ゼラチン及び充填剤を含み、かつ、
有機溶媒の残留物が存在しない、新規の安定な医薬製剤に関する。TECHNICAL FIELD [0001] The present invention comprises levothyroxine sodium, gelatin and a filler, and
The present invention relates to a novel stable pharmaceutical formulation free of organic solvent residues.

【０００２】 この新規な製剤は安定性が向上しており、甲状腺ホルモン製剤として使用でき
る。[0002] This new formulation has improved stability and can be used as a thyroid hormone formulation.

【０００３】 この新規な製剤は、その上、試験管内での活性化合物の放出が良い。[0003] The new formulations also have a good release of the active compounds in vitro.

【０００４】 この発明は、同じ目的に使用する公知の薬剤よりも良好な性質を有する、医薬
製剤の形の新規な薬剤を利用できるようにする目的に基づいたものである。The invention is based on the object of making available new drugs in the form of pharmaceutical preparations which have better properties than known drugs used for the same purpose.

【０００５】 （背景技術） 米連邦公報第６２巻，１５号，１９９７年８月１４日の４３５３５頁で、保健
衛生省，食品、医薬委員会（Department of Health and Human Services, Food
and Drug Administration）は、レボチロキシンナトリゥムを含み経口投与する
アメリカ市場で入手可能な製品には安定性の問題があるので２０％までの過剰投
与量で存在させねばならないこと、及び製造業者は適宜の新しい投与形態を開発
しなければならないことを公表した。レボチロキシンＮａ錠の試験管内放出に関
する必要がさらに高まっている。Pharmacopeial Forum の予稿モノグラフ（Phar
m. View, 1995, 21, 1459-1461）では、テスト１（リン酸塩緩衝液，ｐＨ７．４
，８０分で＞５５％）のほかにテスト２（水，４５分で＞７０％）も示すことを
提案している。[0005] Background Art [0005] US Patent Publication No. 62, No. 15, p. 43535, Aug. 14, 1997, states the Department of Health and Human Services, Food Commission.
and Drug Administration) states that products available in the U.S. market containing orally administered levothyroxine sodium must be present in overdoses of up to 20% due to stability problems, and It has been announced that appropriate new dosage forms must be developed. There is a growing need for in vitro release of levothyroxine Na tablets. Pharmacopeial Forum draft monograph (Phar
m. View, 1995, 21, 1459-1461), test 1 (phosphate buffer, pH 7.4).
,> 55% at 80 minutes) as well as Test 2 (water,> 70% at 45 minutes).

【０００６】 この目的は新規な製剤の発見により達成された。[0006] This object has been achieved by the discovery of new formulations.

【０００７】 グリシン、炭水化物及び無機塩などの他の添加物を有するチロキシン−含有製
剤が国際出願特許ＷＯ ９７ １７ ９５１に開示されている。[0007] A thyroxine-containing formulation with other additives such as glycine, carbohydrates and inorganic salts is disclosed in international application patent WO 9717951.

【０００８】 チオ硫酸塩で安定化された別のチロキシン製剤がドイツ特許ＤＥ １９５ ４
１ １２８に記載されている。Another thyroxine preparation stabilized with thiosulphate is described in German Patent DE 195 4
1 128.

【０００９】 レボチロキシンナトリゥムと沃化カリゥムを含む配合製剤が米国特許ＵＳ５，
６３５，２０９で知られている。チロキシン／シクロデキストリン錯体を含む別
のチロキシン含有調合物がＷＯ ９７ １９ ７０３に記載されている。[0009] A combination preparation containing levothyroxine sodium and potassium iodide is disclosed in US Pat.
635,209. Another thyroxine-containing formulation comprising a thyroxine / cyclodextrin complex is described in WO 9719703.

【００１０】 （発明の開示） 本発明による医薬調合物は、レボチロキシンナトリゥムの他にリオチロニンナ
トリゥムを含むこともできる。DISCLOSURE OF THE INVENTION In addition to levothyroxine sodium, the pharmaceutical composition according to the invention can also comprise liothyronine sodium.

【００１１】 本発明は、好ましくは前述したような医薬製剤に関するものであり、該製剤が
５−４００μｇ、好ましくは１０−３００μｇ、特に好ましくは２５−３００μ
ｇのレボチロキシンナトリゥムを含むことを特徴とする。The present invention preferably relates to a pharmaceutical preparation as described above, wherein said preparation comprises 5-400 μg, preferably 10-300 μg, particularly preferably 25-300 μg.
g of levothyroxine sodium.

【００１２】 本発明はさらに、好ましくは該製剤が５−２５μｍの粒子サイズを有する微細
なレボチロキシンナトリゥムを含むことを特徴とする、前述したような医薬製剤
に関する。The present invention further relates to a pharmaceutical formulation as described above, preferably characterized in that the formulation comprises fine levothyroxine sodium having a particle size of 5-25 μm.

【００１３】 さらに本発明は、好ましくは該製剤がラクトース及び／又はとうもろこし澱粉
及び／又は微晶質のセルロースからなる群から選ばれる充填剤を含むことを特徴
とする、前述の医薬製剤に関する。The invention further relates to the aforementioned pharmaceutical preparation, characterized in that said preparation preferably comprises a filler selected from the group consisting of lactose and / or corn starch and / or microcrystalline cellulose.

【００１４】 特に好ましい医薬製剤は、錠剤の形の固体製剤であることを特徴とするもので
ある。Particularly preferred pharmaceutical preparations are characterized in that they are solid preparations in the form of tablets.

【００１５】 特に好ましい実施態様では、２５，５０，７５，１００，１２５，１５０，１
７５又は２００μｇのレボチロキシンナトリゥムを含む。In particularly preferred embodiments, 25, 50, 75, 100, 125, 150, 1
Contains 75 or 200 μg of levothyroxine sodium.

【００１６】 活性化合物は光、熱及び酸素に対して不安定である。この既知の不安定性のた
め、活性化合物は調合物中に５％までの過剰服用（投与）量で存在させる。Active compounds are unstable to light, heat and oxygen. Due to this known instability, the active compound is present in the formulation in an overdose (dose) of up to 5%.

【００１７】 本発明による製剤は、バインダーとしてゼラチンを使用すると驚く程安定性が
高くなる。The formulations according to the invention are surprisingly more stable when gelatin is used as binder.

【００１８】 もしゼラチンをメトセル（メチルセルロース）などの他の慣用のバインダーに
代えると、安定性調査のスタート時点でさえ活性化合物含量の減少が検出され、
さらに、副成物の合計量が増加する。If the gelatin is replaced by another conventional binder such as Methocel (methylcellulose), a decrease in the active compound content is detected even at the start of the stability study,
Furthermore, the total amount of by-products increases.

【００１９】 例えば、ゼラチンがメトセルで代替されている１００μｇバッチ中の活性化合
物の出発値を測定すると、予期の１０５％ではなく１００．４８％しか発見され
ない。For example, when measuring the starting value of the active compound in a 100 μg batch in which gelatin is replaced by Methocel, only 100.48% is found instead of the expected 105%.

【００２０】 安定性調査によれば、レボチロキシンナトリゥムを含む本発明の錠剤は、３０
℃未満の温度で貯蔵するなら少くとも２年間安定であることがわかった。According to stability studies, tablets of the present invention containing levothyroxine sodium were found to contain 30%
It has been found that storage at temperatures below 0 ° C. is stable for at least 2 years.

【００２１】 さらに、活性化合物を微細化した形で用いると、活性化合物レボチロキシンナ
トリゥムの放出が驚く程良くなる。レボチロキシンナトリゥムは、通例、水及び
エタノールの両方に少ししか溶けない。しかしながら、粒子サイズが５−２５μ
ｍ（９５％まで）の間であると、活性化合物の放出は、テスト１で＞９０％まで
起り（リン酸塩緩衝液）、テスト２では＞８０％に達する（水）。Furthermore, when the active compound is used in finely divided form, the release of the active compound levothyroxine sodium is surprisingly good. Levothyroxine sodium is typically poorly soluble in both water and ethanol. However, when the particle size is 5-25μ
m (up to 95%), the release of the active compound takes place in test 1 to> 90% (phosphate buffer) and in test 2 to> 80% (water).

【００２２】 意外にも、本発明の組成物は有機溶媒を使用しないで製造することもできる。
本発明方法に使用する水を例えばメタノールなどの有機溶媒に代えると、温度２
５℃、相対湿度６０％で１年間貯蔵後の試験バッチではレボチロキシンナトリゥ
ム含量が１０％減少するのがみられる。Surprisingly, the compositions according to the invention can also be prepared without using organic solvents.
When the water used in the method of the present invention is replaced by an organic solvent such as methanol, for example,
A 10% decrease in levothyroxine sodium content is seen in the test batch after one year of storage at 5 ° C. and 60% relative humidity.

【００２３】 本発明による医薬製剤のための好適な充填剤としては、ラクトース、とうもろ
こし澱粉及び／又は微晶質セルロースが好ましく、個々の充填剤としてもよいし
、また互に配合した充填剤としてもよい。前記したように、特に望ましい医薬製
剤はとうもろこし澱粉およびラクトースを含むものである。Suitable fillers for the pharmaceutical preparation according to the invention are preferably lactose, corn starch and / or microcrystalline cellulose, either as individual fillers or as fillers mixed with one another. Good. As noted above, a particularly desirable pharmaceutical formulation is one containing corn starch and lactose.

【００２４】 本発明はまた、レボチロキシンナトリゥムと場合によってはリオチロニンナト
リゥムとを含む医薬製剤の製造方法にも関し、該方法は、ゼラチン水溶液中に懸
濁した形で存在するレボチロキシンナトリゥムと場合によってはリオチロニンナ
トリゥムとを流動床造粒器中の充填剤の上に噴霧し、次いで崩壊剤（disintegra
nt）及び減摩剤を混ぜ、この混合物を圧縮して錠剤にすることを特徴とする。The present invention also relates to a method of preparing a pharmaceutical preparation comprising levothyroxine sodium and optionally liothyronine sodium, the method comprising providing levothyroxine sodium and levothyronine sodium in a suspended form in an aqueous gelatin solution. Spray thyroxine sodium and possibly liothyronine sodium onto the filler in a fluid bed granulator and then disintegrate
nt) and a lubricant, and compressing the mixture into tablets.

【００２５】 本発明はさらに、使用する崩壊剤がクロスカルメロースナトリゥム（croscarm
ellose sodium）であり、使用する潤滑剤（lubricant）がステアリン酸マグネシ
ゥムであることを特徴とする、前記方法に関する。The present invention further provides that the disintegrant used is croscarmellose sodium.
ellose sodium), and the lubricant used is magnesium stearate.

【００２６】 さらに例えば結合剤、酸化防止剤、着色剤、潤滑剤、甘味料及び／又は芳香物
質などの賦形剤又は補助剤を加えることができる。In addition, excipients or auxiliaries such as, for example, binders, antioxidants, colorants, lubricants, sweeteners and / or fragrances can be added.

【００２７】 望ましい滑剤（glidant）又は潤滑剤は、例えばタルク、澱粉、ステアリン酸
マグネシゥム又はステアリン酸カルシゥム、ホウ酸、パラフィン、カカオ脂、マ
クロゴル（macrogol）、ロイシン又は安息香酸ナトリゥムであり、ステアリン酸
マグネシゥムが極めて特に望ましい。Preferred glidants or lubricants are, for example, talc, starch, magnesium stearate or calcium stearate, boric acid, paraffin, cocoa butter, macrogol, leucine or sodium benzoate, and magnesium stearate. Is very particularly desirable.

【００２８】 （実施例） 以下の実施例は、本発明の医薬製剤の製造と組成物に関する。実施例１ 例えば２００万個の錠剤を製造するためには次の各量が必要である。Examples The following examples relate to the preparation and composition of the pharmaceutical formulation of the present invention. Example 1 For example, to produce 2 million tablets, the following amounts are required.

【００２９】[0029]

【表１】 [Table 1]

【００３０】 ＊ ５％過剰投与量のレボチロキシンナトリゥムを別に含む。* Includes a separate 5% overdose of levothyroxine sodium.

【００３１】 ＊＊ 水を乾燥によって再度除去。** Water is removed again by drying.

【００３２】 製造： １．ゼラチンを８０−１００℃の温度で約９０％の水に溶かす。レボチロキシン
ナトリゥムを室温で約１０％の水に懸濁させる。次いでこの懸濁液を５０℃（±
５℃）で前記ゼラチン水溶液に加える。このようにして得られた懸濁液（＝造粒
液）の温度は４５−５０℃である。 ２．ラクトース及びとうもろこし澱粉を流動床造粒器中に入れる。前記造粒液を
この粉末に噴霧する。この噴霧操作の間、造粒液の温度を４０−５０℃の間に保
つ。造粒中、入口温度を約７０℃（±５℃）に保ち、出口温度を２０−４０℃の
間に保つ。噴霧圧力は３−５バールである。噴霧終了後、出口温度が約４０℃に
達するまで顆粒を乾燥させる。Manufacturing: The gelatin is dissolved in about 90% water at a temperature of 80-100 ° C. Levothyroxine sodium is suspended in about 10% water at room temperature. The suspension was then cooled to 50 ° C (±
5 ° C.). The temperature of the suspension (= granulation liquid) thus obtained is 45-50 ° C. 2. Place lactose and corn starch in a fluid bed granulator. The granulation liquid is sprayed on the powder. During this spraying operation, the temperature of the granulation liquid is kept between 40-50 ° C. During granulation, the inlet temperature is kept at about 70 ° C (± 5 ° C) and the outlet temperature is kept between 20-40 ° C. The spray pressure is 3-5 bar. After the end of spraying, the granules are dried until the outlet temperature reaches about 40 ° C.

【００３３】 乾燥顆粒を次いで公知方法により篩分（１ｍｍ）する（＝混合物ａ）。The dried granules are then sieved (1 mm) in a known manner (= mixture a).

【００３４】 クロスカルメロースナトリゥムとステアリン酸マグネシゥムを同様に篩分する
。次いでこの成分をドラムミキサー中で１０分間混合物ａと一緒に混合する。[0034] Croscarmellose sodium and magnesium stearate are similarly sieved. This component is then mixed with the mixture a for 10 minutes in a drum mixer.

【００３５】 最後にこの圧縮準備ができた混合物を圧縮して錠剤にする。実施例２ １００μｇのレボチロキシンナトリゥムを含む１００ｍｇ（±３ｍｇ）錠剤の
組成： レボチロキシンナトリゥム ０．１００ｍｇ ラクトース１水和物 ６５．９０ ｍｇ とうもろこし澱粉 ２５．００ ｍｇ ゼラチン ５．００ ｍｇ クロスカルメロースナトリゥム ３．５０ ｍｇ ステアリン酸マグネシゥム ０．５０ ｍｇ １００．００ ｍｇ レボチロキシンナトリゥムはほぼ５％過剰投与量で存在させる。実施例３ １００μｇのレボチロキシンナトリゥムを含む１００ｍｇ（±３ｍｇ）錠剤の
組成： レボチロキシンナトリゥム ０．１００ｍｇ リオチロニンナトリゥム ０．０２０ｍｇ ラクトース１水化物 ６５．８８ ｍｇ とうもろこし澱粉 ２５．００ ｍｇ ゼラチン ５．００ ｍｇ クロスカルメロースナトリゥム ３．５０ ｍｇ ステアリン酸マグネシゥム ０．５０ ｍｇ １００．００ ｍｇ レボチロキシンナトリゥムは約５％過剰投与量にあるようにする。Finally, the compression-ready mixture is compressed into tablets. Example 2 Composition of 100 mg (± 3 mg) tablets containing 100 μg of levothyroxine sodium: levothyroxine sodium 0.100 mg lactose monohydrate 65.90 mg corn starch 25.00 mg gelatin 5.00 mg cross Carmellose sodium 3.50 mg Magnesium stearate 0.50 mg 100.00 mg Levothyroxine sodium is present in an approximately 5% excess dose. Example 3 Composition of 100 mg (± 3 mg) tablets containing 100 μg levothyroxine sodium: levothyroxine sodium 0.100 mg liothyronine sodium 0.020 mg lactose monohydrate 65.88 mg corn starch 25.00 mg gelatin 5.00 mg croscarmellose sodium 3.50 mg magnesium stearate 0.50 mg 100.00 mg levothyroxine sodium should be in about 5% overdose.

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ａ６１Ｋ 47/42 Ａ６１Ｋ 47/42 (81)指定国 ＥＰ(ＡＴ，ＢＥ，ＣＨ，ＣＹ， ＤＥ，ＤＫ，ＥＳ，ＦＩ，ＦＲ，ＧＢ，ＧＲ，ＩＥ，Ｉ Ｔ，ＬＵ，ＭＣ，ＮＬ，ＰＴ，ＳＥ)，ＯＡ(ＢＦ，ＢＪ ，ＣＦ，ＣＧ，ＣＩ，ＣＭ，ＧＡ，ＧＮ，ＧＷ，ＭＬ， ＭＲ，ＮＥ，ＳＮ，ＴＤ，ＴＧ)，ＡＰ(ＧＨ，ＧＭ，Ｋ Ｅ，ＬＳ，ＭＷ，ＳＤ，ＳＬ，ＳＺ，ＵＧ，ＺＷ)，Ｅ Ａ(ＡＭ，ＡＺ，ＢＹ，ＫＧ，ＫＺ，ＭＤ，ＲＵ，ＴＪ ，ＴＭ)，ＡＥ，ＡＬ，ＡＭ，ＡＴ，ＡＵ，ＡＺ，ＢＡ ，ＢＢ，ＢＧ，ＢＲ，ＢＹ，ＣＡ，ＣＨ，ＣＮ，ＣＵ， ＣＺ，ＤＥ，ＤＫ，ＥＥ，ＥＳ，ＦＩ，ＧＢ，ＧＤ，Ｇ Ｅ，ＧＨ，ＧＭ，ＨＲ，ＨＵ，ＩＤ，ＩＬ，ＩＮ，ＩＳ ，ＪＰ，ＫＥ，ＫＧ，ＫＰ，ＫＲ，ＫＺ，ＬＣ，ＬＫ， ＬＲ，ＬＳ，ＬＴ，ＬＵ，ＬＶ，ＭＤ，ＭＧ，ＭＫ，Ｍ Ｎ，ＭＷ，ＭＸ，ＮＯ，ＮＺ，ＰＬ，ＰＴ，ＲＯ，ＲＵ ，ＳＤ，ＳＥ，ＳＧ，ＳＩ，ＳＫ，ＳＬ，ＴＪ，ＴＭ， ＴＲ，ＴＴ，ＵＡ，ＵＧ，ＵＳ，ＵＺ，ＶＮ，ＹＵ，Ｚ Ａ，ＺＷ (71)出願人 Ｆｒａｎｋｆｕｒｔｅｒ Ｓｔｒ． 250， Ｄ−64293 Ｄａｒｍｓｔａｄｔ，Ｆｅｄ ｅｒａｌ Ｒｅｐｕｂｌｉｃ ｏｆ Ｇｅ ｒｍａｎｙ (72)発明者 ニシュヴィッツ、 マリオン ドイツ連邦共和国 デー−64291 ダルム シュタット グレーザーヴェーク 17 Ｆターム(参考） 4C076 AA36 BB01 CC30 DD41C DD67 EE31 EE32B EE38 EE42 FF05 FF06 FF09 FF36 GG12 GG14 GG16 4C206 AA01 AA02 FA53 MA03 MA05 MA55 NA03 ZC06 ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 7 Identification symbol FI Theme court ゛ (Reference) A61K 47/42 A61K 47/42 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, F I, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV , MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (71) Applicant Frankfighter Str. 250, D-64293 Darmstadt, Federal Republic of Germany (72) Inventor Nischwitz, Marion Germany Day-64291 Darmstadt Glaserweg 17 F-term (reference) 4C076 AA36 BB01 CC30 DD41C DD42EE05 EE31 EE31 FF06 FF09 FF36 GG12 GG14 GG16 4C206 AA01 AA02 FA53 MA03 MA05 MA55 NA03 ZC06

Claims (8)

【特許請求の範囲】[Claims] 【請求項１】 レボチロキシンナトリゥム、ゼラチン及び充填剤を含み、か
つ、有機溶媒残留物が存在しないことを特徴とする、医薬製剤。1. A pharmaceutical preparation comprising levothyroxine sodium, gelatin and a filler, characterized in being free of organic solvent residues. 【請求項２】 リオチロニンナトリゥムも任意に含まれている、請求項１に
記載の製剤。2. The formulation according to claim 1, wherein liothyronine sodium is also optionally contained. 【請求項３】 レボチロキシンナトリゥムが５−４００μｇ含まれている、
請求項１に記載の製剤。3. Levothyroxine sodium is contained in an amount of 5-400 μg,
The preparation according to claim 1. 【請求項４】 粒子のサイズが５−２５μｍの微細化されたレボチロキシン
ナトリゥムが含まれている、請求項１に記載の製剤。4. The formulation of claim 1, wherein the formulation comprises micronized levothyroxine sodium having a particle size of 5-25 μm. 【請求項５】 ラクトース及び／又はとうもろこし澱粉及び／又は微晶質の
セルロースからなる群から選ばれる充填剤が含まれている、請求項１に記載の製
剤。5. The preparation according to claim 1, further comprising a filler selected from the group consisting of lactose and / or corn starch and / or microcrystalline cellulose. 【請求項６】 製剤が錠剤の形の固体の製剤である、請求項１ないし３のい
ずれか１項に記載の製剤。6. The formulation according to claim 1, wherein the formulation is a solid formulation in the form of a tablet. 【請求項７】 ゼラチン水溶液中に懸濁状で存在するレボチロキシンナトリ
ゥムと任意のリオチロニンナトリゥムとを、流動床造粒中の充填剤の上に噴霧し
、次いで崩壊剤及び潤滑剤を混合し、該混合物を圧縮して錠剤にすることを特徴
とする、医薬製剤の製造方法。7. Spraying levothyroxine sodium and optional liothyronine sodium, present in suspension in an aqueous gelatin solution, onto the filler during fluid bed granulation, then disintegrating and lubricating A method for producing a pharmaceutical preparation, comprising mixing an agent and compressing the mixture into a tablet. 【請求項８】 使用する崩壊剤がクロスカルメロースナトリゥムであり、か
つ、使用する潤滑剤がステアリン酸マグネシゥムである、請求項５に記載の方法
。8. The method according to claim 5, wherein the disintegrant used is croscarmellose sodium and the lubricant used is magnesium stearate.
JP2000549216A 1998-05-15 1999-05-05 Pharmaceutical formulation containing levothyroxine sodium Expired - Lifetime JP4709379B2 (en)

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